Free‐radical‐induced oxidative damage has been implicated as an important mechanism responsible for the toxicity of both active and passive smoking. Cigarette smoke contains short‐ and long‐lived radicals and can stimulate cellular production of highly reactive oxygen species. One of the antioxidant enzymes that is protective against reactive oxygen‐induced damage is manganese superoxide dismutase (MnSOD), which is located in the mitochondria of mammalian cells. The present study was conducted to examine the role of oxidative damage in cigarette smoke toxicity. A mouse fibroblast cell line (C3H10T1/2) and its MnSOD‐transfected, enzymatically active clone, R2 cells, which possessed about fivefold greater MnSOD activity, were used to test the cytotoxicity of condensates from mainstream (MS‐CSC) and sidestream (SS‐CSC) cigarette smoke. Growth and respiration studies of the two test cell lines showed that the R2 cells grew to a higher cell density and exhibited greater oxygen uptake than the parent cells under normal growth conditions. Both smoke condensates were cytotoxic to test cells, but SS‐CSC exhibited slightly greater toxicity, and R2 cells were significantly less susceptible to SS‐CSC toxicity than the parent cells. SS‐CSC caused a slightly greater inhibition of respiratory activity in parent cells than in R2 cells. These results suggest a significant contribution of oxidative damage in SS‐CSC cytotoxicity.